Despite aggressive treatment protocols based on powerful drug combinations currently available, the incidence of HIV-1 infection continues to rise and it is now pandemic in many of the developing nations. These protocols are highly successful at reducing viral loads, even to undetectable levels, but they do not eliminate quiescent reservoirs of viral infection. Thus, treatments must be lifelong, are costly, and are accompanied by significant toxic side effects. This situation requires consideration of alternative strategies and it remains a consensus in the biomedical research community that an immunotherapeutic vaccine will eventually provide the most effective, affordable long-term approach to halting the spread of HIV/AIDS. The collective experience to date is that HIV is immunogenic; it provokes an immune response in most infected individuals, but this immune response must be considered to be ineffective. Current vaccine trials consist of immunization with attenuated native virus, virion proteins or their peptide fragments; so far none have proven to be successful. Stronger immunogens are required. One approach not yet tried involves alterations of the peptide sequence of native viral T cell epitopes to create optimized, highly immunogenic peptide analogues that provoke strong T cell mediated immunity that eliminates viral infected cells in the body. MSI has developed the technology and provided proof-of-concept for screening combinatorial peptide libraries with T cell lines and clones having a clinically relevant specificity to identify panels of highly immunogenic peptides that are more effective in stimulating immune responses against the native peptide sequence. The specific Aims are 1) to identify optimized mimic peptides for several HLA-A2 restricted epitopes of conserved HIV proteins; 2) assess their immunogenicity in HLA-A2 transgenic mice; and 3) explore strategies for further enhancement of immunogenicity. Ultimately, this peptide sequence information will be incorporated into a therapeutic/ prophylactic multi-epitope vaccine formulation based on multiple peptides, fusion proteins or DNA sequences in viral vectors.